What is the most likely diagnosis for a young adult patient presenting with a negative streptococcal (STREP) test, anterior and posterior cervical lymphadenopathy, red and exudative throat, splenomegaly, and petechiae in the oral mucosa?

Infectious Mononucleosis (Epstein-Barr Virus)

The most likely diagnosis is infectious mononucleosis caused by Epstein-Barr virus (EBV), given the constellation of negative streptococcal test, bilateral cervical lymphadenopathy (particularly posterior chain involvement), exudative pharyngitis, splenomegaly, and palatal petechiae in a young adult patient. 1, 2

Clinical Reasoning

The clinical presentation strongly points away from streptococcal pharyngitis and toward a viral etiology, specifically EBV infectious mononucleosis:

Key Distinguishing Features Present

• Posterior cervical lymphadenopathy is highly characteristic of EBV infectious mononucleosis—100% of EBV-positive cases in pediatric studies demonstrated posterior cervical node involvement, which is not typical of streptococcal pharyngitis 3

• Splenomegaly occurs in approximately 58% of EBV cases and is not a feature of streptococcal pharyngitis 3

• Palatal petechiae can occur in both conditions, but when combined with the other findings (especially splenomegaly and posterior cervical nodes), strongly favors EBV 1, 4

• Negative streptococcal test effectively rules out Group A streptococcal pharyngitis, as the Infectious Diseases Society of America guidelines emphasize that a negative test provides reassurance of likely viral etiology 5

Classic EBV Infectious Mononucleosis Presentation

The patient demonstrates the classic triad plus additional features:

• Pharyngitis with exudates (can be exudative or nonexudative in EBV) 6
• Fever and significant fatigue (hallmark symptoms) 1, 2
• Lymphadenopathy involving both anterior and posterior cervical chains, with posterior chain involvement being particularly suggestive 1, 3
• Splenomegaly (present in 50-60% of cases) 4, 3

Diagnostic Confirmation Strategy

Immediate next steps should include:

• Complete blood count with differential looking for >40% lymphocytes and >10% atypical lymphocytes, which strongly supports the diagnosis 2

• Heterophile antibody test (Monospot) has 87% sensitivity and 91% specificity, though it can be falsely negative in the first week of illness 2, 4

• Liver transaminases are elevated in most EBV cases and increase clinical suspicion when heterophile test is negative 2

• If heterophile antibody is negative but clinical suspicion remains high, EBV-specific viral capsid antigen (VCA) IgM and IgG antibodies provide definitive diagnosis with higher sensitivity and specificity 2, 4

Critical Management Considerations

Immediate Safety Concerns

• Assess for airway compromise, as pharyngeal edema can cause obstruction (most common reason for hospitalization) 4

• Evaluate for splenic rupture risk—the patient must avoid contact/collision sports and strenuous physical activity for at least 3-4 weeks from symptom onset 1, 2

Treatment Approach

• Supportive care only: adequate hydration, analgesics, antipyretics, and rest guided by the patient's energy level 1, 2

• Avoid routine corticosteroids and antivirals—these are not recommended for uncomplicated infectious mononucleosis 1, 2

• Never prescribe ampicillin or amoxicillin if there is any consideration of EBV, as these cause a characteristic maculopapular rash in 80-100% of patients with infectious mononucleosis

Common Diagnostic Pitfall

The exudative pharyngitis can mimic streptococcal pharyngitis, but the presence of splenomegaly, posterior cervical lymphadenopathy, and negative strep test should immediately redirect thinking toward EBV rather than prompting empiric antibiotic treatment 5, 1. The Infectious Diseases Society of America emphasizes that the vast majority of pharyngitis cases are viral and do not require antibiotics 5.